Thymic Composition Predicts Radiation Pneumonitis in Locally Advanced NSCLC

Durvalumab consolidation after concurrent chemoradiotherapy (cCRT) is standard for unresectable stage III NSCLC; however, radiation pneumonitis (RP) remains a major treatment-limiting toxicity. Lung dosimetry incompletely explains the risk of toxicity. Recent studies have established radiographic thymic health as clinically relevant in cancer, but its relationship to treatment-related toxicity remains unclear. We evaluated whether percent thymic tissue (pTT), an interpretable CT-derived measure of residual thymic tissue, is associated with severe pneumonitis after cCRT in NSCLC.

We analyzed patients with locally advanced NSCLC treated with cCRT with or without durvalumab in RTOG 0617 (n = 453) and at the Memorial Sloan Kettering Cancer Center (MSKCC, n = 230). pTT was derived from pretreatment CT using autosegmentation and Gaussian mixture modeling. Logistic regression with restricted cubic splines assessed the associations of pTT, mean radiation dose to the thymic region, and volume of lungs receiving more than or equal to 20 Gy (lung V20) with high-grade (≥3) pneumonitis.

Higher pTT was associated with lower severe pneumonitis rates, independent of lung V20. Grade 3+ pneumonitis occurred in 8.0% versus 3.1% of low- versus high-pTT patients in RTOG 0617 (p = 0.03) and in 13.9% versus 5.2% at the MSKCC (p = 0.04). Patients with both low pTT and high lung V20 had the highest severe pneumonitis rates. Mean radiation dose to the thymic region revealed a weaker, nonlinear relationship with pneumonitis risk.

pTT is an interpretable, host-specific radiographic biomarker associated with severe pneumonitis after cCRT in NSCLC. Incorporating pTT into risk stratification may improve individualized treatment planning and support the safer delivery of curative-intent therapy in locally advanced NSCLC.